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In patients undergoing percutaneous coronary intervention (PCI), intensifying antiplatelet therapy based on platelet reactivity testing reduces cardiovascular mortality and stent thrombosis, according to a meta-analysis published online June 15, 2012, ahead of print in the International Journal of Cardiology. In particular, the higher patients’ baseline risk of stent thrombosis, the more they benefit from testing.

For the study, a team led by Dániel Aradi, MD, PhD, of the University of Pécs (Pécs, Hungary), analyzed data from 10 randomized trials (4,213 patients) published from 2008 to 2011 that reported the clinical impact of intensified antiplatelet therapy, based on ADP-specific platelet reactivity testing, compared with standard-dose clopidogrel. The studies varied considerably in protocol, with differences in the risk profile of the patient population, primary endpoint, platelet function assay used, and intensified antiplatelet strategy applied.

More Is Better

In the pooled results, the intensified therapy reduced cardiovascular mortality, Academic Research Consortium-defined definite or probable stent thrombosis, and nonfatal MI, as well as the composite of those endpoints, without increasing the rate of major bleeding. Overall, the net clinical benefit (cardiovascular death, MI, definite or probable stent thrombosis, and major bleeding) also favored the intensified regimen (table 1).

Table 1. Clinical Outcomes After Intensified Antiplatelet Therapy

 
Analysis of treatment-specific effects showed that repeat loading doses of clopidogrel reduced early stent thrombosis (OR 0.10; P = 0.008) and MI (OR 0.09; P = 0.006), glycoprotein IIb/IIIa inhibitor (GPI) infusion decreased periprocedural myonecrosis (OR 0.42; P = 0.002), and higher maintenance doses of clopidogrel reduced cardiovascular mortality (OR 0.42; P = 0.03).

No Impact from Trial Diversity

The trials were similar with regard to the effects of platelet reactivity-guided therapy on cardiovascular death, stent thrombosis, or major bleeding. Similarly, the results remained consistent after looking at multiple patient subgroups and study factors such as length of follow-up and study size.

However, the authors report, trends were observed toward less ischemic benefit and higher bleeding risk in studies that included lower-risk patients, prompting them to perform meta-regression analyses to assess the effect of baseline risk. These analyses demonstrate that trials that included patients at higher stent thrombosis risk showed a greater net benefit, while the advantage of intensified treatment disappeared among patients at low stent thrombosis risk.

“Therefore, our results mainly support the importance of platelet reactivity testing in patients at high risk for [stent thrombosis], where the intensified antiplatelet therapy based on platelet reactivity testing seems safe and effective,” the authors write. Such testing is also economically attractive given the cost difference between generic clopidogrel and the new-generation ADP receptor antagonists, they add.

Targeted Platelet Testing

In a telephone interview with TCTMD, study coauthor Matthew J. Price, MD, of Scripps Clinic (La Jolla, CA), acknowledged that the results of any meta-analysis should be “taken with a grain of salt.” Nonetheless, he said, “certain themes emerge that can help us apply platelet function testing outside of definitive randomized clinical trials.”

One such theme is that patients at the highest risk for cardiovascular events may be the ones who have the most to gain from testing, he explained. Another—and one that in particular lends credence to the analysis—is that the endpoint showing the strongest and most consistent improvement with intensified treatment, namely stent thrombosis, is the one that is most specifically related to the efficacy of antiplatelet therapy.

“The key question is: Can you identify the patients who are at high baseline ischemic risk where measuring platelet function may provide clinical benefit?” Dr. Price said. Unfortunately, he added, with the advent of generic clopidogrel and the current indications for prasugrel and ticagrelor, it is challenging to obtain funding for a large trial with enough power to clearly answer that question.

“In the absence of a definitive randomized trial, we have to use signals from the data we have to create a framework where we can incorporate platelet function testing [into patient management] in order to improve clinical outcomes,” he noted.

Skepticism Given Prior Negative Trials

Looking at the same data, Deepak L. Bhatt, MD, MPH, of Brigham and Women's Hospital (Boston, MA), came to a different conclusion.

“I believe the core finding, that in high-risk patients more potent antiplatelet therapy is better than less potent therapy,” he told TCTMD in a telephone interview. “But we sort of already know that from randomized trials.” Moreover, the study strongly suggests a benefit of platelet function testing, he added. But a definitive prospective randomized trial with positive results is needed before physicians would be justified in adopting the strategy routinely, he insisted, adding, “What we have now are 2 large, well-done trials—GRAVITAS and TRIGGER PCI—and both are negative.”

The management of PCI patients is complex and many issues might trump any incremental information gained from platelet function testing, Dr. Bhatt explained. “For the time being, the way to go is to base [decisions about whether to change antiplatelet therapy] on clinical factors,” he said.

Nonetheless, there may be specific circumstances in which testing is justified, Dr. Bhatt observed—for example, when a patient has suffered multiple stent thromboses and antiplatelet compliance and stent malapposition are not at issue. “That patient can’t wait for a randomized trial,” he observed. “But in general I think it’s premature to routinely start testing because we don’t really know what to do with that information. And what we do based on our gut feeling could be wrong—it might increase bleeding without reducing ischemic events.

“To me, this meta-analysis is hypothesis-generating, not proof,” he concluded.

Study Details 

To intensify standard therapy, 2 trials used periprocedural GPI infusion, 2 administered repeat loading doses of 600 mg of clopidogrel, 4 used an increased maintenance dose of clopidogrel, and 1 switched to prasugrel. Platelet function testing was performed using VerifyNow (Accumetrics, San Diego, CA), Multiplate (Roche/Verum Diagnostica, Munich, Germany), VASP, or light transmission aggregometry.

If periprocedural GPI or repeated clopidogrel loading doses were used, outcomes were tabulated at 30 days after intensified treatment initiation; otherwise they were estimated at the end of the intensified protocol. 

Related Stories:

• One-Month Platelet Reactivity After PCI Key Risk Factor for Future Events
• TRIGGER-PCI Published: Halted Trial Questions Platelet Testing in Stable Patients
• GRAVITAS Published: No Benefit from High-Dose Clopidogrel in Poor Responders

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